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rs77722678

From SNPedia

Likely Pathogenic Variant for Hypochondroplasia
Orientationminus
Stabilizedminus
Geno Mag Summary
(C;C) 6.6 Hypochondroplasia
(C;T) 5.5 Hypochondroplasia
(T;T) 0 common in clinvar
ReferenceGRCh38 38.1/142
Chromosome4
Position1805643
GeneFGFR3
is asnp
is mentioned by
dbSNPrs77722678
ebirs77722678
HLIrs77722678
Exacrs77722678
Varsomers77722678
Maprs77722678
PheGenIrs77722678
hapmaprs77722678
1000 genomesrs77722678
hgdprs77722678
ensemblrs77722678
gopubmedrs77722678
geneviewrs77722678
scholarrs77722678
googlers77722678
pharmgkbrs77722678
gwascentralrs77722678
openSNPrs77722678
23andMers77722678
23andMe allrs77722678
SNP Nexus

SNPshotrs77722678
SNPdbers77722678
MSV3drs77722678
GWAS Ctlgrs77722678
Merged fromRs121913107, Rs121913110
Max Magnitude6.6

rs77722678, also known as c.1619A>G, p.Asn540Ser and N540S, represents a rare mutation in the FGFR3 gene on chromosome 4. The rare (minor) allele has been associated with a form of hypochondroplasia, inherited in an autosomal dominant manner.

OMIM134934
Desc
Variant0023
Relatedalso
ClinVar
Risk rs77722678(C,G;C,G)
Alt rs77722678(C,G;C,G)
Reference rs77722678(T;T)
Significance Pathogenic
Disease Hypochondroplasia
Variation info
Gene FGFR3
CLNDBN Hypochondroplasia
Reversed 1
HGVS NC_000004.11:g.1807370A>C; NC_000004.11:g.1807370A>G
CLNSRC OMIM Allelic Variant
CLNACC RCV000017753.28, RCV000017758.28,


[PMID 10777366] Mortier G, et al. (2000) - The p.N540S alteration was seen in a family with a clinical diagnosis of hypochondroplasia. The daughter had short stature, prominent forehead, low nasal bridge, anteroposteriorly flattened thorax, and lumbar hyperlordosis. Skeletal examination showed mild shortening of the tubular bones, minimal increase in lumbar interpedicular distance, and anteroposterior shortening of the lumbar. The father was short with macrocephaly and a prominent forehead, low nasal bridge, muscular build, and broad thorax. He had the same skeletal findings as his daughter, but also presented with long proximal portion of the fibula and remarkably short femoral necks.

Domain Information - The p.N540 amino acid is located in the molecular break region of the kinase domain and it is part of a complex loop/hinge region. It is solvent-exposed and interacts with charged residues. The role of the kinase domain is to stabilize the inactive state over the active state of the protein by forming a dynamic hydrogen bond network. A loss of the dynamic network of the hydrogen bonds results in over-activation of the kinase which is correlated with hypochondroplasia [PMID 23972473] [PMID 26220993]. The known likely pathogenic alteration, p.N540K, disrupts the hydrogen bonding network as does the p.N540S alteration. Other variants in this region that result in activating the protein/gain-of-function have been shown to result in the spectrum of hypochondraplasia [PMID 23972473] [PMID 26220993]. Even a mild disruption of this region corresponds to pathogenicity as seen in the likely pathogenic alteration, p.I538V [PMID 9222758].